Supravalvular aortic stenosis (SVAS) is a heart defect that develops before birth. This defect is a narrowing (stenosis) of the large blood vessel that carries blood from the heart to the rest of the body (the aorta). The condition is described as supravalvular because the section of the aorta that is narrowed is located just above the valve that connects the aorta with the heart (the aortic valve). Some people with SVAS also have defects in other blood vessels, most commonly stenosis of the artery from the heart to the lungs (the pulmonary artery). An abnormal heart sound during a heartbeat (heart murmur) can often be heard during a chest exam. If SVAS is not treated, the aortic narrowing can lead to shortness of breath, chest pain, and ultimately heart failure.

The severity of SVAS varies considerably, even among family members. Some affected individuals die in infancy, while others never experience symptoms of the disorder.

Mutations in the ELN gene cause SVAS. The ELN gene provides instructions for making a protein called tropoelastin. Multiple copies of the tropoelastin protein attach to one another and are processed to form a mature protein called elastin. Elastin is the major component of elastic fibers, which are slender bundles of proteins that provide strength and flexibility to connective tissue (tissue that supports the body's joints and organs). Elastic fibers are found in the intricate lattice that forms in the spaces between cells (the extracellular matrix), where they give structural support to organs and tissues such as the heart, skin, lungs, ligaments, and blood vessels. Elastic fibers make up approximately 50 percent of the aorta, the rest being primarily muscle cells called vascular smooth muscle cells that line the aorta. Together, elastic fibers and vascular smooth muscle cells provide flexibility and resilience to the aorta.

Most of the ELN gene mutations that cause SVAS lead to a decrease in the production of tropoelastin. A shortage of tropoelastin reduces the amount of mature elastin protein that is processed and available for forming elastic fibers. As a result, elastic fibers that make up the aorta are thinner than normal. To compensate, the smooth muscle cells that line the aorta increase in number, making the aorta thicker and narrower than usual. A thickened aorta is less flexible and resilient to the stress of constant blood flow and pumping of the heart. Over time, the wall of the aorta can become damaged. Aortic narrowing causes the heart to work harder to pump blood through the aorta, resulting in the signs and symptoms of SVAS.

Normal Function

The ELN gene provides instructions for making a protein called tropoelastin. Multiple copies of the tropoelastin protein attach to one another and are processed to form a mature protein called elastin. Elastin is the major component of elastic fibers, which are a major component of the tissue that supports the body's joints and organs (connective tissue). Elastic fibers are found in the intricate lattice that forms in the spaces between cells (the extracellular matrix). They can be stretched and then snap back into place, which is how they provide resilience and flexibility to organs and tissues such as the heart, skin, lungs, ligaments, and blood vessels.

Health Conditions Related to Genetic Changes

Cutis laxa

At least 18 variants (also known as mutations) in the ELN gene have been identified in people with a skin disorder called cutis laxa. ELN gene variants cause a form of the condition called autosomal dominant cutis laxa type 1 (ADCL1), which is characterized by loose, sagging skin; an increased risk of an abnormal bulging (an aneurysm) in a large blood vessel called the aorta; and a lung disease called emphysema, which can make it difficult to breathe.

The ELN gene variants that cause ADCL1 lead to the production of an abnormal version of the tropoelastin protein. The abnormal protein is less able to be incorporated into mature elastin, which impairs the formation of strong elastic fibers. This defect in elastic fibers weakens connective tissue in the skin and blood vessels and makes it difficult for tissue to snap back into shape when stretched. The problems with connective tissue underlie the major features of cutis laxa.

Supravalvular aortic stenosis

More than 70 variants in the ELN gene have been found to cause supravalvular aortic stenosis (SVAS), a blood vessel defect most commonly identified in infancy or early childhood that is characterized by a narrowing of the large blood vessel that carries blood from the heart to the rest of the body (the aorta). Most of the ELN gene variants that cause SVAS lead to a decrease in the production of tropoelastin. A shortage of tropoelastin reduces the amount of mature elastin protein that is processed and available for forming elastic fibers. As a result, elastic fibers that make up the aorta are thinner than normal. To compensate, the smooth muscle cells that line the aorta increase in number, making the aorta thicker and narrower than usual. A thickened aorta is less flexible and delivers blood too forcefully, which can damage organs. Aortic narrowing causes the heart to work harder to pump blood through the aorta, which can lead to shortness of breath, chest pain, and ultimately heart failure.

7q11.23 duplication syndrome

The ELN gene is located in a region of chromosome 7 that is duplicated in people with 7q11.23 duplication syndrome. As a result of this duplication, people with 7q11.23 duplication syndrome have an extra copy of the ELN gene and several other genes in each cell. 7q11.23 duplication syndrome can cause a variety of neurological and behavioral problems as well as other abnormalities.

Some individuals with 7q11.23 duplication syndrome have mild to moderate enlargement (dilatation) of the aorta; this enlargement can get worse over time. Aortic dilatation in people with this condition can very rarely lead to life-threatening complications if the wall of the aorta separates into layers (aortic dissection) or breaks open (ruptures). Individuals with 7q11.23 duplication may have other heart or blood vessel abnormalities. An extra copy of the ELN gene in each cell may lead to the production of a greater than normal amount of tropoelastin, and researchers suggest that this excess might be related to the increased risk for aortic dilatation in 7q11.23 duplication syndrome; however, the specific cause of the aortic dilatation remains unclear.

Williams syndrome

The ELN gene is located in a region of chromosome 7 that is deleted in people with Williams syndrome, which is a developmental disorder that is characterized by mild to moderate intellectual disability or learning problems, unique personality characteristics, distinctive facial features, and heart and blood vessel (cardiovascular) problems. As a result of the deletion, people with Williams syndrome are missing one copy of the ELN gene in each cell. This loss reduces the production of elastin by approximately half, which disrupts the normal structure of elastic fibers in many connective tissues. As a result, large blood vessels such as the aorta are often thicker and less resilient than normal. These vessels can narrow (as in SVAS, described above), increasing the resistance to normal blood flow and leading to serious medical problems.

In addition to cardiovascular problems like SVAS, a loss of the ELN gene is associated with other connective tissue abnormalities, such as joint problems, soft skin, and mild lung problems. Loss of the ELN gene may also play a role in other features of the condition, such as premature skin wrinkling and abnormalities of the digestive tract.

Other Names for This Gene

• elastin
• ELN_HUMAN
• tropoelastin

Genomic Location

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. However, some people who inherit the altered gene never develop features of SVAS. (This situation is known as reduced penetrance.)

In some cases, a person inherits the mutation from one parent who has the mutation. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family.

SVAS occurs in 1 in 20,000 newborns worldwide.